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Matrix Metalloproteinase Inhibitors

a technology of matrix metalloproteinase and inhibitor, which is applied in the direction of biocide, drug composition, immunological disorders, etc., can solve the problems of more enzyme production and subsequent tissue damag

Inactive Publication Date: 2009-03-26
GLAXO GROUP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a new group of chemical compounds that can inhibit the activity of matrix metalloproteinase enzymes (MMPs). These enzymes play a major role in the degradation of connective tissue and inflammation. The compounds are designed to treat disease states where MMP activity results in degradation of connective tissue and inflammation. The invention provides new compounds that can be used for the treatment of MMP-related diseases.

Problems solved by technology

Enzyme activation can not only initiate tissue damage but induce increased inflammatory cell infiltration into the tissue, leading to more enzyme production and subsequent tissue damage.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

5-Biphenyl-4-yl-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic acid

[0088]

[0089]Potassium phthalimide (8.8 mg, 60 μmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl) oxy]ethyl}pentanoate (28.4 mg, 50 μmol) in dimethylformamide (0.5 mL) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue taken up in dichloromethane (0.5 mL). Trifloroacetic acid (0.5 mL) was added in one portion and the resulting solution stirred for 1 h at room temperature. The volatiles were evaporated and the residue purified by mass directed auto-preparative HPLC to give the title compound as a white solid (6.0 mg, 27%). LC / MS: 3.43 min; z / e 444, calcd (M+1) 444. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55 (1H), 7.50 (1H), 7.45 (2H), 7.30 (1H), 7.25 (4H), 3.85 (3H), ...

example 2

5-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)ethyl]pentanoic acid

[0090]

[0091]Prepared by an analogous reaction sequence to example 1. LC / MS: 2.96 min; Z / e 423, calcd (M+1) 423.

example 3

5-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyri midin-1(2H)-yl)ethyl]pentanoic acid

[0092]

[0093]Prepared by an analogous reaction sequence to example 1. LC / MS: 2.98 min; z / e 423, calcd (M+1) 423.

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Abstract

The present invention relates to compounds of Formula (I):or pharmaceutically acceptable salts thereof, corresponding preparation processes, pharmaceutical formulations and methods for use as inhibitors of matrix metallproteinase enzymes (MMPs).

Description

CROSS REFERENCE TO PRIOR APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 571,443 filed 13 Mar. 2006 (pending) which is a 371 application of PCT / EP2004 / 010319 filed 10 Sep. 2004 which claims priority to GB0321538.1 filed 13 Sep. 2003.FIELD OF THE INVENTION[0002]This invention relates to novel chemical compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.[0003]The compounds of the invention are inhibitors of matrix metalloproteinase enzymes (MMPs).BACKGROUND OF THE INVENTION[0004]Matrix metalloproteinase enzymes play a major role in extracellular matrix component degradation and remodelling. Examples of MMPs include collagenase 1, 2 and 3, gelatinase A and B, stromelysin 1,2 and 3, matrilysin, macrophage metalloelastase, enamelysin and membrane type 1,2,3 and 4 MMP. The enzymes are secreted by connective tissue cells and inflammatory cells. Enzyme activation can not only initiate tissue da...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/513A61K31/4035A61K31/505A61K31/506A61P29/00C07D209/48C07D239/54C07D403/10C07D405/10
CPCC07D209/48C07D405/10C07D403/10C07D239/54A61P29/00A61P37/00A61P37/02A61P37/06A61P43/00A61K31/4035A61K31/513A61K31/343
Inventor GAINES, SIMONHOLMES, IAN PETERMARTIN, STEPHEN LEWISWATSON, STEPHEN PAUL
Owner GLAXO GROUP LTD